Neuroprotective agents for the prevention and treatment of neurodegenerative diseases

ABSTRACT

Disclosed herein are methods of treating neurodegenerative diseases comprising administering to the subject a compound having the structure: 
     
       
         
         
             
             
         
       
     
     wherein α and R 1 -R 8  are described herein, or a compound having the structure: 
     
       
         
         
             
             
         
       
     
     wherein Y, Z, and R 21 , R 24 , R 25 , and R 31 -R 33  are described herein.

This application claims the benefit of U.S. Provisional Application No.61/137,658, filed Aug. 1, 2008, the content of of which in its entiretyis hereby incorporated by reference.

Throughout this application, certain publications are referenced. Fullcitations for these publications may be found immediately preceding theclaims. The disclosures of these publications in their entireties arehereby incorporated by reference into this application in order todescribe more fully the state-of-the art to which this inventionrelates.

BACKGROUND OF THE INVENTION

It has been estimated that neurodegenerative diseases presently affect20 million individuals worldwide. The cost for medical care of patientswith Alzheimer's disease (AD), for example, was $91 billion in 2005 andis predicted to increase to $160 billion by 2010 (Burke 2007). Despiteconsiderable research on the etiology and pharmacologic treatment ofthese diseases, no therapy is known to delay their progression (Schapiraand Olanow 2004, Burke 2007). Recently, enhancing the activity of aubiquitous regulatory protein Akt kinase has beneficial effects uponneurons of the substantia nigra of the midbrain of animals. Theincreased signaling of Akt mediates the improvement in the health ofthese neuronal cells in adult normal and aged neurons and confers almostcomplete protection against neurotoxin induced cell death in rodents(Ries et al, 2006).

AD and other neurodegenerative diseases are called tauopathies becausethey are characterized by the accumulation of aggregates of the tauprotein in neurons. Tau proteins promote the assembly and stabilizationof microtubular structures in neurons. The function of tau is regulatedby phosphorylation at multiple serine and threonine sites (Sontag et al1996; Tian and Wang 2002). The state of phosphorylation of tauinfluences its ability to bind to and enhance the polymerization ofmicrotubules in neurons (Gong et al 2005; Meske et al 2008).

The basis by which increased Akt signaling produces neuroprotection isnot certain (Burke 2007). It has been suggested that increased Aktsignaling in neurons results in a decrease in the generation of depositsof neurofilaments within neurons leading to their dysfunction andeventual death (Gong et al, 2005. These filaments are composed of astructural protein called Tau. Tau proteins are susceptible tohyper-phosphorylation. Hyper-phosphorylation of tau proteins rendersthem inactive and results in their aggregation into paired helicalfilaments. These tangles of tau protein along with plaques of β-amyloid(AB) are the characteristic pathologic features of AD and the othertauopathies (Gong et al 2005).

Control of tau activity by phosphorylation is accomplished by severalserine-threonine kinases, particularly glycogen synthase kinase-3β(GSK-3β). GSK-3β itself is regulated by other serine-threonine kinasesespecially Akt (Grimes and Jope 2001; Liu et al 2005). Activated(phosphorylated) Akt maintains GSK-3β in an inhibited (phosphorylatedstate). A decrease in Akt activity, that is reduced amounts ofphosphorylated Akt, results in activation, that is, decreasedphosphorylation of GSK-3β. Activated GSK-3β leads tohyper-phosphorylation of tau, which leads to neuronal cell death (Kaytorand Orr 2002; Baki et al 2008).

There is strong evidence from studies of human Alzheimer's disease andfrom a mouse model of Alzheimer's disease that failure of adequatelevels of phosphorylation of GSK-3β by Akt results inhyper-phosphorylation of tau, generation of tau and amyloid plaques, andneuronal degeneration and death. In early onset familial AD (FAD) thereis a defect in presenilins, trans-membrane proteins critical to normaldevelopment (Shen et al, 1997; Wong et al 1998). A member of thisfamily, presenilin-1 (PS1), regulates PI3K/Akt signaling (Sherrington etal 1995; Baki et al 2004; Kang et al 2005; Uemura et al 2007). Inprimary neuronal cultures of cells from PS1 −/− mice, Baki et al (2008)showed that there was inadequate PI3K-Akt signaling resulting indecreased phosphorylation of GSK-3β, hyper-phosphorylation of tau, andprogressive neurodegeneration. The addition of normal presenilin-1 or ofPI3K-Akt increased GSK-3β phosphorylation and suppressed neuronal celldeath.

Ries et al. (2006) showed that increasing the concentration of activatedAkt inhibits cell death of dopamine neurons of the substantia nigra inmouse model of Parkinson's disease induced by 6-hydroxy dopamine.Increasing Akt activity in the brain of normal adult and also aged miceenhanced the integrity and function of existing dopamine neurons (Rieset al., 2006). In a mouse model of AD, animals with geneticallyengineered increased amounts of GSK-3β in the forebrain have all thehistologic and, to the extent that they can be assessed in the mouse,functional defects of human AD. Elimination of over-expression of GSK-3βby suppression of the transgene results in a return toward normal of allhistologic and functional signs of AD (Engel et al 2006).

Neurodegenerative diseases such as AD are frequently characterized byimpaired learning and memory. The mechanism(s) responsible for thesemost troublesome symptoms are associated with death of neuronal cells.At a molecular level, the basis for changes in memory formation andconsolidation has been linked to the activity of histone deacetylaseschromatin structures (Korzus et al, 2004; Levenson et al, 2004).Beglopoulos and Shen (2006) found that inhibitors of phosphodiesterase 4and histone deacetylases reduce memory deficits and neurodegeneration inanimal models of AD affecting cAMP response element (CRE) genes.Recently, Fischer et al (2007) reported improved learning behavior andaccess to long-term memories after significant neuronal loss and brainatrophy can be reestablished in a mouse model by environmentalenrichment and by treatment with inhibitors of histone deacetylases (seereviews and commentaries by Sweat, 2007; Mangan and Levenson 2007;Albert 2007; Abel and Zukin; 2008).

Acetylation and deacetylation have a critical role in regulation of geneexpression, cellular proliferation, development and differentiation,with aberrant deacetylation leading to a multitude of disorders (Abeland Zukin, 2008). Histone deacetylase inhibitors (HDACi) haveanti-inflammatory and neuroprotective effects in models of stroke andAlzheimer's disease (AD) (Abel and Zukin, 2008). Inhibitors of proteinphosphatase 2A (PP2Ai), primarily the shellfish toxin, okadaic acid,have neuroprotective effects in some model systems but are injurious inothers (Tian and Wang, 2002).

Thus, there is substantial evidence that AD is a pathologic conditionresulting from inadequate activity of the enzyme Akt and excessiveactivity of GSK-3β and that reduction of GSK-3β activity may reduce theseverity of precipitated tau proteins, with a lessening of neurologicaldeficit. In addition, there appears to be a poorly understood componentof neurodegenerative diseases related to excessive histone deacetylaseactivity, or at least a condition of reduced acetylation of certainhistones that is corrected by increased acetylation resulting inimproved learning and memory. Non-toxic drugs that protect and fosterthe survival of acute and chronically diseased neurons are urgentlyneeded.

The compounds described herein reduce the activity of GSK-3β andincrease the acetylation of neuronal histones.

SUMMARY OF THE INVENTION

This invention disclosed herein provides a method of treating a subjectwith a neurodegenerative disease comprising administering to the subjecta compound having the structure

wherein bond α is present or absent; R₁ and R₂ is each independently H,O⁻ or OR₉, where R₉ is H, alkyl, alkenyl, alkynyl or aryl, or R₁ and R₂together are ═O; R₃ and R₄ are each different, and each is OH, O⁻, OR₉,SH, S⁻, SR₉,

where X is O, S, NR₁₀, or N⁺R₁₀R₁₀, where each R₁₀ is independently H,alkyl, substituted C₂-C₁₂ alkyl, alkenyl, substituted C₄-C₁₂ alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl where thesubstituent is other than chloro when R₁ and R₂ are ═O,

-   -   —CH₂CN, —CH₂CO₂R₁₁, —CH₂COR₁₁, —NHR₁₁ or —NH⁺(R₁₁)₂, where each        R₁₁ is independently alkyl, alkenyl or alkynyl, each of which is        substituted or unsubstituted, or H; R₅ and R₆ is each        independently H, OH, or R₅ and R₆ taken together are ═O; and R₇        and R₈ is each independently H, F, Cl, Br, SO₂Ph, CO₂CH₃, or        SR₁₂, where R₁₂ is H, aryl or a substituted or unsubstituted        alkyl, alkenyl or alkynyl, or a salt, enantiomer or zwitterion        of the compound, or a compound having the structure

wherein n is 1-10; Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl,SO₂R₂₆, NO₂, trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl; Z is

R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently H, C₁-C₆alkyl, or C₃-C₈ cycloalkyl; R₂₄ is OH or SH; and R₂₅, R₃₁, R₃₂, and R₃₃are each independently H, OH, SH, F, Cl, SO₂R₃₄, NO₂, trifluoromethyl,methoxy, or CO—R₃₄, wherein R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈cycloalkyl, or aryl, or a salt of the compound, in an amount effectiveto treat the subject.

This invention also provides a method for reducing the amount of GSK-3βin a neural cell comprising contacting the cell with an effective amountof a compound having the structure

wherein bond α is present or absent; R₁ and R₂ is each independently H,O⁻ or OR₉, where R₉ is H, alkyl, alkenyl, alkynyl or aryl, or R₁ and R₂together are ═O; R₃ and R₄ are each different, and each is OH, O⁻, OR₉,SH, S⁻, SR₉,

where X is O, S, NR₁₀, or N⁺R₁₀R₁₀, where each R₁₀ is independently H,alkyl, substituted C₂-C₁₂ alkyl, alkenyl, substituted C₄-C₁₂ alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl where thesubstituent is other than chloro when R₁ and R₂ are ═O,

-   -   —CH₂CN, —CH₂CO₂R₁₁, —CH₂COR₁₁, —NHR₁₁ or —NH⁺(R₁₁)₂, where each        R₁₁ is independently alkyl, alkenyl or alkynyl, each of which is        substituted or unsubstituted, or H; R₅ and R₆ is each        independently H, OH, or R₅ and R₆ taken together are ═O; and R₇        and R₈ is each independently H, F, Cl, Br, SO₂Ph, CO₂CH₃, or        SR₁₂, where R₁₂ is H, aryl or a substituted or unsubstituted        alkyl, alkenyl or alkynyl,or a salt, enantiomer or zwitterion of        the compound, or a compound having the structure

wherein n is 1-10; Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl,SO₂R₂₆, NO₂, trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl; Z is

R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently H, C₁-C₆alkyl, or C₃-C₈ cycloalkyl; R₂₄ is OH or SH; and R₂₅, R₃₁, R₃₂, and R₃₃are each independently H, OH, SH, F, Cl, SO₂R₃₄, NO₂, trifluoromethyl,methoxy, or CO—R₃₄, wherein R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈cycloalkyl, or aryl, or a salt of the compound, so as to thereby reducethe amount of GSK-3β in the neural cell.

Also provided is a method for increasing the amount of phosphorylatedAkt in a neural cell comprising contacting the neural cell with aneffective amount of a compound having the structure

wherein bond α is present or absent; R₁ and R₂ is each independently H,O⁻ or OR₉, where R₉ is H, alkyl, alkenyl, alkynyl or aryl, or R₁ and R₂together are ⊚O; R₃ and R₄ are each different, and each is OH, O⁻, OR₉,SH, S⁻, SR₉,

where X is O, S, NR₁₀, or N⁺R₁₀R₁₀ where each R₁₀ is independently H,alkyl, substituted C₂-C₁₂ alkyl, alkenyl, substituted C₄-C₁₂ alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl where thesubstituent is other than chloro when R₁ and R₂ are ═O,

—CH₂CN, —CH₂CO₂R₁₁, —CH₂COR₁₁, —NHR₁₁ or —NH⁺(R₁₁)₂, where each R₁₁ isindependently alkyl, alkenyl or alkynyl, each of which is substituted orunsubstituted, or H; R₅ and R₆ is each independently H, OH, or R₅ and R₆taken together are ═O; and

-   -   R₇ and R₈ is each independently H, F, Cl, Br, SO₂Ph, CO₂CH₃, or        SR₁₂, where R₁₂ is H, aryl or a substituted or unsubstituted        alkyl, alkenyl or alkynyl,or a salt, enantiomer or zwitterion of        the compound, or a compound having the structure

wherein n is 1-10; Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl,SO₂R₂₆, NO₂, trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl; Z is

R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently H, C₁-C₆alkyl, or C₃-C₈ cycloalkyl; R₂₄ is OH or SH; and R₂₅, R₃₁, R₃₂, and R₃₃are each independently H, OH, SH, F, Cl, SO₂R₃₄, NO₂, trifluoromethyl,methoxy, or CO—R₃₄, wherein R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈cycloalkyl, or aryl, or a salt of the compound, so as to therebyincrease the amount of phosphorylated Akt in the neural cell.

This invention further provides a method for reducing thephosphorylation of tau in a neural cell, comprising contacting theneural cell with an effective amount of a compound having the structure

wherein bond α is present or absent; R₁ and R₂ is each independently H,O⁻or OR₉, where R₉ is H, alkyl, alkenyl, alkynyl or aryl, or R₁ and R₂together are ═O; R₃ and R₄ are each different, and each is OH, O⁻, OR₉,SH, S⁻, SR₉,

where X is O, S, NR₁₀, or N⁺R₁₀R₁₀, where each R₁₀ is independently H,alkyl, substituted C₂-C₁₂ alkyl, alkenyl, substituted C₄-C₁₂ alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl where thesubstituent is other than chloro when R₁ and R₂ are ═O,

-   -   —CH₂CN, —CH₂CO₂R₁₁, —CH₂COR₁₁, —NHR₁₁ or —NH⁺(R₁₁)₂, where each        R₁₁ is independently alkyl, alkenyl or alkynyl, each of which is        substituted or unsubstituted, or H; R₅ and R₆ is each        independently H, OH, or R₅ and R₆ taken together are ═O; and R₇        and R₈ is each independently H, F, Cl, Br, SO₂Ph, CO₂CH₃, or        SR₁₂, where R₁₂ is H, aryl or a substituted or unsubstituted        alkyl, alkenyl or alkynyl, or a salt, enantiomer or zwitterion        of the compound, or a compound having the structure

wherein n is 1-10; Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl,SO₂R₂₆, NO₂, trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl; Z is

R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently H, C₁-C₆alkyl, or C₃-C₈ cycloalkyl; R₂₄ is OH or SH; and R₂₅, R₃₁, R₃₂, and R₃₃are each independently H, OH, SH, F, Cl, SO₂R₃₄, NO₂, trifluoromethyl,methoxy, or CO—R₃₄, wherein R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈cycloalkyl, or aryl, or a salt of the compound, so as to thereby reducethe phosphorylation of tau in the neural cell.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Induction of phosphorylated Akt by Compound 100 in DAOY cells inculture.

The medulloblastoma cells, DAOY, in culture were exposed to Compound100, Compound 205 or vehicle alone. After 4 hours western blots weremade for p-Akt, total Akt, and beta actin. Control cells (C) showed onlytrace amounts of p-Akt and substantial amounts of total Akt and betaactin. Exposure to Compound 205, a compound with no anti-PP2A activity,had no effect. Exposure to Compound 100 revealed induction of p-Akt andan increase in total Akt relative to beta actin.

FIG. 2: Induction of phosphorylated Akt by Compound 100 in DAOY cellsgrowing as xenografts in SCID mice.

SCID mice with human medulloblastoma cells, DAOY, implantedsubcutaneously were treated with 0.03 mg/20 gram mouse with Compound 100or vehicle alone. After 4 hours and 24 hours western blots were made forp-Akt, total Akt, and beta actin. Control cells (C) at both time points(only 24 hour point shown) had only trace amounts of p-Akt andsubstantial amounts of total Akt and beta actin. Exposure to Compound100 revealed induction of p-Akt and an increase in total Akt relative tobeta actin.

FIG. 3: Induction of phosphorylated Akt by Compound-100 in U87 cells inculture.

The human glioblastoma cells, U87, were exposed to compound 100 orvehicle alone. After 4 hours western blots were made for p-Akt, totalAkt, and beta actin. Control cells (C) showed only trace amounts ofp-Akt and substantial amounts of total Akt and beta actin. Exposure toCompund 100 revealed induction of p-Akt and an increase in total Aktrelative to beta actin.

FIG. 4: Induction of phosphorylated Akt by Compound-100 in U87 cellsgrowing as xenografts in SCID mice.

SCID mice with human glioblastoma cells, U87, implanted subcutaneouslywere treated with 0.03 mg/20 gram mouse with Compound 100 or vehiclealone. After 4 hours, western blots were made for p-Akt, total Akt, andbeta actin. Control cells (C) showed only trace amounts of p-Akt andsubstantial amounts of total Akt and beta actin. Exposure to Compound100 revealed induction of p-Akt and an increase in total Akt relative tobeta actin.

FIG. 5: Induction of acetylation of Histone 3 and Histone 4 in normalmouse brain by Compound 100 and Compound 102.

Normal mice were treated with Compound 100 and Compound 102, 0.03 mg/20gram mouse. After 4 hours of exposure, treated and control animals(vehicle alone) animals were sacrificed and western blots for acetylatedhistone 3 and histone 4 were made. Both drugs increased acetylation ofthe histones compared to control tissue.

FIG. 6. Photomicrographs of primary embryonal rat cortical neuronalcells at 23 days subjected to environmental stress by exposure to growthfactor deficient medium for 1 hour on day 3 of culture.

FIG. 7. Average number of primary embryonal rat cortical neuronal cellsat 3, 6, 13, and 23 days in culture (n=4).

All cultures were exposed to growth factor deficient medium for 1 houron day 3 followed by of culture in complete medium containing nosupplement (control), drug vehicle (0.05% DMSO), compound 102 (500 nM),or compound 201 (500 nM). Only exposure to compound 201 resulted instatistically significant (p<=0.01) protection of cell integrity.

FIGS. 8-10. Calcium response to acute exposure of 200 uM glutamate inthe presence of vehicle (0.05% DMSO).

FIG. 8 shows photomicrographs of one field of cells in which change incalcium flux was measured in individual cells (FIG. 9), and thenaveraged (FIG. 10).

FIGS. 11-14. Calcium response to acute exposure to 200 uM glutamate inthe presence of 500 nm Compound 102.

FIG. 11 shows photomicrographs of one field of cells in which change incalcium flux was measured in individual cells (FIG. 12), then averaged(FIG. 13), and the average response was compared to the DMSO control(FIG. 14). The presence of compound 102 significantly enhanced theresponse to glutamate (p<=0.001) in this particular study.

FIGS. 15-18. Calcium response to acute exposure to 200 uM glutamate inthe presence of 500 nm Compound 201.

FIG. 15 shows photomicrographs of one field of cells in which change incalcium flux was measured in individual cells (FIG. 16), then averaged(FIG. 17), and the average response was compared to the DMSO control(FIG. 18). The presence of compound 201 significantly enhanced theresponse to glutamate (p<=0.001) in this particular study.

FIG. 19. Bar graph showing the average % increase in response toglutamate exposure of 4 separate experiments.

Compound 201 significantly enhanced the response to glutamate (p<=0.001)whereas compound 102 was less effective but still had a significanteffect of the response at p<=0.01

DETAILED DESCRIPTION OF THE INVENTION Embodiments

This invention provides a method of treating a subject with aneurodegenerative disease comprising administering to the subject acompound having the structure

wherein

bond α is present or absent;

R₁ and R₂ is each independently H, O⁻ or OR₉,

-   -   where R₉ is H, alkyl, alkenyl, alkynyl or aryl, or R₁ and R₂        together are ═O;

R₃ and R₄ are each different, and each is OH, O⁻, OR₉, SH, S⁻, SR₉,

where X is O, S, NR₁₀, or N⁺R₁₀R₁₀,

-   -   where each R₁₀ is independently H, alkyl, substituted C₂-C₁₂        alkyl, alkenyl, substituted C₄-C₁₂ alkenyl, alkynyl, substituted        alkynyl, aryl, substituted aryl where the substituent is other        than chloro when R₁ and R₂ are ═O,

-   -   —CH₂CN, —CH₂CO₂R₁₁, —CH₂COR₁₁, —NHR₁₁ or —NH⁺(R₁₁)₂, where each        R₁₁ is independently alkyl, alkenyl or alkynyl, each of which is        substituted or unsubstituted, or H;    -   R₅ and R₆ is each independently H, OH, or R₅ and R₆ taken        together are ═O; and    -   R₇ and R₈ is each independently H, F, Cl, Br, SO₂Ph, CO₂CH₃, or        SR₁₂,    -   where R₁₂ is H, aryl or a substituted or    -   unsubstituted alkyl, alkenyl or alkynyl, or a salt, enantiomer        or zwitterion of the compound, or a compound having the        structure

wherein

n is 1-10;

-   -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;    -   z is

-   -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently    -   H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F,    -   Cl, SO₂R₃₄, NO₂, trifluoromethyl, methoxy, or CO—R₃₄, wherein    -   R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl, or a        salt of the compound,    -   in an amount effective to treat the subject.

In an embodiment of the above method, the compound has the structure

-   -   wherein    -   n is 1-9;    -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl,        SO₂R₃₄, NO₂, trifluoromethyl, methoxy, or CO—R₃₄, wherein R₃₄ is        alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl.

In another embodiement of the above method, the compound has thestructure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and

R₂₅ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂, trifluoromethyl, methoxy, orCO—R₂₆, wherein R₂₆ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, oraryl.

In a further embodiment of the above method, the compound has thestructure

-   -   wherein    -   n is 1-9;    -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently    -   H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and

R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl,trifluoromethyl, methoxy, or CO—R₃₄, wherein R₃₄ is alkyl, alkenyl,alkynyl, C₃-C₈ cycloalkyl, or aryl; In further embodiment, the compoundhas the structure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅ is H, OH, SH, F, Cl, trifluoromethyl, methoxy, or CO—R₂₆,        wherein R₂₆ is alkyl, alkenyl, alkynyl, or C₃-C₈ cycloalkyl, or        aryl.

In another embodiment, the compound has the structure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅ is H, OH, SH, F, Cl, trifluoromethyl, methoxy, or CO—R₂₆,        wherein R₂₆ is alkyl, alkenyl, alkynyl, or C₃-C₈ cycloalkyl, or        aryl.

In an embodiment of the above method, subject is a mammal.

In another embodiment of the above method, the neurodegenerative diseaseis Alzheimer's disease, Mild Cognitive Impairment, Parkinsons Disease,Frontotemporal Dementia, Dementia, or Lewy Body Dementia. In a furtherembodiment the neurodegenerative disease is Alzheimer's disease.

Another embodiment of the above method further comprises administeringto the subject an NMDA receptor antagonist, an acetylcholinesteraseinhibitor, an anti-amyloid antibody, a 5-HT6 antagonist, a gammasecretase inhibitor, a beta secretase inhibitor, or an inhibitor ofaggregation of amyloid-β peptide. In another embodiment, the methodfurther comprises administering to the subject a tau aggregationinhibitor.

Examples of known NMDA receptor agonists include, but are not limitedto, memantine. Examples of known acetylcholinesterase inhibitorsinclude, but are not limited to, galantamine, rivastigmine, anddonapezil. Examples of a tau aggregation inhibitor include, but are notlimited to, rember.

In another embodiment of the above method, the neurodegenerative diseaseis Parkinson's disease.

Another embodiment of the above method further comprises administeringto the subject a dopamine receptor agonist.

The invention provides a method for reducing the amount of active GSK-3Bin a neural cell comprising contacting the cell with an effective amountof a compound having the structure

-   -   wherein    -   bond α is present or absent;    -   R₁ and R₂ is each independently H, O⁻ or OR₉,        -   where R₉ is H, alkyl, alkenyl, alkynyl or aryl, or R₁ and R₂            together are ═O;    -   R₃ and R₄ are each different, and each is OH, O⁻, OR₉, SH, S⁻,        SR₉,

-   -   where X is O, S, NR₁₀, or N⁺R₁₀R₁₀, where each R₁₀ is        independently H, alkyl, substituted C₂-C₁₂ alkyl, alkenyl,        substituted C₄-C₁₂ alkenyl, alkynyl, substituted alkynyl, aryl,        substituted aryl where the substituent is other than chloro when        R₁ and R₂ are ═O,

-   -   —CH₂CN, —CH₂CO₂R₁₁, —CH₂COR₁₁, —NHR₁₁ or —NH⁺(R₁₁)₂, where each        R₁₁ is independently alkyl, alkenyl or alkynyl, each of which is        substituted or unsubstituted, or H;

R₅ and R₆ is each independently H, OH, or R₅ and R₆ taken together are═O; and

R₇ and R₈ is each independently H, F, Cl, Br, SO₂Ph, CO₂CH₃, or SR₁₂,

-   -   where R₁₂ is H, aryl or a substituted or unsubstituted    -   alkyl, alkenyl or alkynyl,

or a salt, enantiomer or zwitterion of the compound, or a compoundhaving the structure

-   -   wherein    -   n is 1-10;    -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;

-   -   z is    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl,        SO₂R₃₄, NO₂, trifluoromethyl, methoxy, or CO—R₃₄, wherein    -   R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl, or a        salt of the compound,

so as to thereby reduce the amount of GSK-3B in the neural cell.

In an embodiment of the above method, the compound has the structure

-   -   wherein    -   n is 1-9;    -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl,        SO₂R₃₄, NO₂, trifluoromethyl, methoxy, or CO—R₃₄, wherein    -   R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl.

In another embodiement of the above method, the compound has thestructure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂, trifluoromethyl, methoxy,        or CO—R₂₆, wherein R₂₆ is alkyl, alkenyl, alkynyl, C₃-C₈        cycloalkyl, or aryl.

In a further embodiment of the above method, the compound has thestructure

-   -   wherein    -   n is 1-9;    -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and

R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl,trifluoromethyl, methoxy, or CO—R₃₄, wherein R₃₄ is alkyl, alkenyl,alkynyl, C₃-C₈ cycloalkyl, or aryl; In further embodiment, the compoundhas the structure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅ is H, OH, SH, F, Cl, trifluoromethyl, methoxy, or CO—R₂₆,        wherein R₂₆ is alkyl, alkenyl, alkynyl, or C₃-C₈ cycloalkyl, or        aryl.

In another embodiment, the compound has the structure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅ is H, OH, SH, F, Cl, trifluoromethyl, methoxy, or CO—R₂₆,        wherein R₂₆ is alkyl, alkenyl, alkynyl, or C₃-C₈ cycloalkyl, or        aryl.

The invention provides a method for increasing the amount ofphosphorylated Akt in a neural cell comprising contacting the neuralcell with an effective amount of a compound having the structure

-   -   wherein    -   bond α is present or absent;    -   R₁ and R₂ is each independently H, O⁻ or OR₉,        -   where R₉ is H, alkyl, alkenyl, alkynyl or aryl, or R₁ and R₂            together are ═O;    -   R₃ and R₄ are each different, and each is OH, O⁻, OR₉, SH, S⁻,        SR₉,

-   -   where X is O, S, NR₁₀, or N⁺R₁₀R₁₀,        -   where each R₁₀ is independently H, alkyl, substituted C₂-C₁₂            alkyl, alkenyl, substituted C₄-C₁₂ alkenyl, alkynyl,            substituted alkynyl, aryl, substituted aryl where the            substituent is other than chloro when R₁ and R₂ are ═O,

-   -   -   —CH₂CN, —CH₂CO₂R₁₁, —CH₂COR₁₁, —NHR¹¹ or —NH⁺(R₁₁)₂, where            each R₁₁ is independently alkyl, alkenyl or alkynyl, each of            which is substituted or unsubstituted, or H;

    -   R₅ and R₆ is each independently H, OH, or R₅ and R₆ taken        together are ═O; and

    -   R₇ and R₈ is each independently H, F, Cl, Br, SO₂Ph, CO₂CH₃, or        SR₁₂,        -   where R₁₂ is H, aryl or a substituted or unsubstituted            alkyl, alkenyl or alkynyl,

    -   or a salt, enantiomer or zwitterion of the compound, or a        compound having the structure

-   -   wherein    -   n is 1-10;    -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;    -   z is

-   -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl,        SO₂R₃₄, NO₂, trifluoromethyl, methoxy, or CO—R₃₄, wherein    -   R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl, or a        salt of the compound,

so as to thereby increase the amount of phosphorylated Akt in the neuralcell.

In an embodiment of the above method, the compound has the structure

-   -   wherein    -   n is 1-9;    -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl,        SO₂R₃₄, NO₂, trifluoromethyl, methoxy, or CO—R₃₄, wherein    -   R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl.

In another embodiement of the above method, the compound has thestructure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂, trifluoromethyl, methoxy,        or CO—R₂₆, wherein R₂₆ is alkyl, alkenyl, alkynyl, C₃-C₈        cycloalkyl, or aryl.

In a further embodiment of the above method, the compound has thestructure

-   -   wherein    -   n is 1-9;    -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and

R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl,trifluoromethyl, methoxy, or CO—R₃₄, wherein R₃₄ is alkyl, alkenyl,alkynyl, C₃-C₈ cycloalkyl, or aryl; In further embodiment, the compoundhas the structure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅ is H, OH, SH, F, Cl, trifluoromethyl, methoxy, or CO—R₂₆,        wherein R₂₆ is alkyl, alkenyl, alkynyl, or C₃-C₈ cycloalkyl, or        aryl.

In another embodiment, the compound has the structure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅ is H, OH, SH, F, Cl, trifluoromethyl, methoxy, or CO—R₂₆,        wherein R₂₆ is alkyl, alkenyl, alkynyl, or C₃-C₈ cycloalkyl, or        aryl.

The invention provides a method for reducing the phosphorylation of Tauprotein in a cell, comprising contacting the cell with an effectiveamount of a compound having the structure

-   -   wherein    -   bond α is present or absent;    -   R₁ and R₂ is each independently H, O⁻ or OR₉,        -   where R₉ is H, alkyl, alkenyl, alkynyl or aryl, or R₁ and R₂            together are ═O;    -   R₃ and R₄ are each different, and each is OH, O⁻, OR₉, SH, S³¹ ,        SR₉,

-   -   where X is O, S, NR₁₀, or N⁺R₁₀R₁₀,        -   where each R₁₀ is independently H, alkyl, substituted C₂-C₁₂            alkyl, alkenyl, substituted C₄-C₁₂ alkenyl, alkynyl,            substituted alkynyl, aryl, substituted aryl where the            substituent is other than chloro when R₁ and R₂ are ═O,

-   -   -   —CH₂CN, —CH₂CO₂R₁₁, —CH₂COR₁₁, —NHR₁₁ or —NH⁺(R₁₁)₂, where            each R₁l is independently alkyl, alkenyl or alkynyl, each of            which is substituted or unsubstituted, or H;

    -   R₅ and R₆ is each independently H, OH, or R₅ and R₆ taken        together are ═O; and

    -   R₇ and R₈ is each independently H, F, Cl, Br, SO₂Ph, CO₂CH₃, or        SR₁₂,        -   where R₁₂ is H, aryl or a substituted or unsubstituted            alkyl, alkenyl or alkynyl,

    -   or a salt, enantiomer or zwitterion of the compound, or a        compound having the structure

-   -   wherein    -   n is 1-10;    -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;    -   z is

-   -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl,        SO₂R₃₄, NO₂, trifluoromethyl, methoxy, or CO—R₃₄, wherein    -   R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl, or a        salt of the compound,so as to thereby reduce the phosphorylation        of tau in the cell.

In an embodiment of the above method, the compound has the structure

-   -   wherein    -   n is 1-9;    -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl,        SO₂R₃₄, NO₂, trifluoromethyl, methoxy, or CO—R₃₄, wherein    -   R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl.

In another embodiement of the above method, the compound has thestructure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂, trifluoromethyl, methoxy,        or CO—R₂₆, wherein R₂₆ is alkyl, alkenyl, alkynyl, C₃-C₈        cycloalkyl, or aryl.

In a further embodiment of the above method, the compound has thestructure

-   -   wherein    -   n is 1-9;    -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and

R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl,trifluoromethyl, methoxy, or CO—R₃₄, wherein R₃₄ is alkyl, alkenyl,alkynyl, C₃-C₈ cycloalkyl, or aryl; In further embodiment, the compoundhas the structure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅ is H, OH, SH, F, Cl, trifluoromethyl, methoxy, or CO—R₂₆,        wherein R₂₆ is alkyl, alkenyl, alkynyl, or C₃-C₈ cycloalkyl, or        aryl.

In another embodiment, the compound has the structure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅ is H, OH, SH, F, Cl, trifluoromethyl, methoxy, or CO—R₂₆,        wherein R₂₆ is alkyl, alkenyl, alkynyl, or C₃-C₈ cycloalkyl, or        aryl.

The invention provides a method for reducing the aggregation of Tauprotein in a cell comprising contacting the cell with an effectiveamount of a compound having the structure

-   -   wherein    -   bond α is present or absent;    -   R₁ and R₂ is each independently H, O⁻ or OR₉,        -   where R₉ is H, alkyl, alkenyl, alkynyl or aryl, or R₁ and R₂            together are ═O;    -   R₃ and R₄ are each different, and each is OH, O⁻, OR₉, SH, S⁻,        SR₉,

-   -   where X is O, S, NR₁₀, or N⁺R₁₀R₁₀,        -   where each R₁o is independently H, alkyl, substituted C₂-C₁₂            alkyl, alkenyl, substituted C₄-C₁₂ alkenyl, alkynyl,            substituted alkynyl, aryl, substituted aryl where the            substituent is other than chloro when R₁ and R₂ are ═O,

-   -   -   —CH₂CN, —CH₂CO₂R₁₁, —CH₂COR₁₁, —NHR₁₁ or —NH⁺(R₁₁)₂, where            each R₁l is independently alkyl, alkenyl or alkynyl, each of            which is substituted or unsubstituted, or H;

    -   R₅ and R₆ is each independently H, OH, or R₅ and R₆ taken        together are ═O; and

    -   R₇ and R₈ is each independently H, F, Cl, Br, SO₂Ph, CO₂CH₃, or        SR₁₂,        -   where R₁₂ is H, aryl or a substituted or unsubstituted            alkyl, alkenyl or alkynyl,

    -   or a salt, enantiomer or zwitterion of the compound, or a        compound having the structure

-   -   wherein    -   n is 1-10;    -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;    -   Z is

-   -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl,        SO₂R₃₄, NO₂, trifluoromethyl, methoxy, or CO—R₃₄, wherein    -   R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl, or a        salt of the compound,

so as to thereby inhibit the aggregation of Tau in the cell.

In an embodiment of the above method, the compound has the structure

-   -   wherein    -   n is 1-9;    -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl,        SO₂R₃₄, NO₂, trifluoromethyl, methoxy, or CO—R₃₄, wherein    -   R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl.

In another embodiement of the above method, the compound has thestructure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂, trifluoromethyl, methoxy,        or CO—R₂₆, wherein R₂₆ is alkyl, alkenyl, alkynyl, C₃-C₈        cycloalkyl, or aryl.

In a further embodiment of the above method, the compound has thestructure

-   -   wherein    -   n is 1-9;    -   Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂,        trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl,        alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and

R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl,trifluoromethyl, methoxy, or CO—R₃₄, wherein R₃₄ is alkyl, alkenyl,alkynyl, C₃-C₈ cycloalkyl, or aryl; In further embodiment, the compoundhas the structure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅ is H, OH, SH, F, Cl, trifluoromethyl, methoxy, or CO—R₂₆,        wherein R₂₆ is alkyl, alkenyl, alkynyl, or C₃-C₈ cycloalkyl, or        aryl.

In another embodiment, the compound has the structure

-   -   wherein    -   n is 1-8;    -   Y is CH or N;    -   R₂₀ is H or OH;    -   R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently        C₁-C₆ alkyl or C₃-C₈ cycloalkyl;    -   R₂₄ is OH or SH; and    -   R₂₅ is H, OH, SH, F, Cl, trifluoromethyl, methoxy, or CO—R₂₆,        wherein R₂₆ is alkyl, alkenyl, alkynyl, or C₃-C₈ cycloalkyl, or        aryl.

In one embodiment of the foregoing methods, the cell is a neural cell.In another embodiment of the foregoing methods, The the cell is in asubject.

In an embodiment of any of the foregoing methods, the compound hasstructure of Compound 100, Compound 100E, Compound 101, Compound 101E,Compound 102, Compound 102E, Compound 103, Compound 103E, Compound 104,Compound 104E, Compound 105, Compound 105E, Compound 106, Compound 106E,Compound 107, Compound 107E, Compound 108 or Compound 108E.

In an embodiment of any of the foregoing methods, the compound has thestructure of Compound 201, Compound 203, Compound 204, Compound 205,Compound 206, Compound 207, Compound 207(a), Compound 208, Compound 209,Compound 210, Compound 211, Compound 212, Compound 213, or Compound 214.

Definitions

Certain embodiments of the disclosed compounds can contain a basicfunctional group, such as amino or alkylamino, and are thus capable offorming pharmaceutically acceptable salts with pharmaceuticallyacceptable acids, or contain an acidic functional group and are thuscapable of forming pharmaceutically acceptable salts with bases. Theinstant compounds therefore may be in a salt form. As used herein, a“salt” is a salt of the instant compounds which has been modified bymaking acid or base salts of the compounds. The salt may bepharmaceutically acceptable. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as phenols. The salts can be made using an organic orinorganic acid. Such acid salts are chlorides, bromides, sulfates,nitrates, phosphates, sulfonates, formates, tartrates, maleates,malates, citrates, benzoates, salicylates, ascorbates, and the like.Phenolate salts are the alkaline earth metal salts, sodium, potassium orlithium. The term “pharmaceutically acceptable salt” in this respect,refers to the relatively non-toxic, inorganic and organic acid or baseaddition salts of compounds of the present invention. These salts can beprepared in situ during the final isolation and purification of thecompounds of the invention, or by separately reacting a purifiedcompound of the invention in its free base or free acid form with asuitable organic or inorganic acid or base, and isolating the salt thusformed. Representative salts include the hydrobromide, hydrochloride,sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate,palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate,glucoheptonate, lactobionate, and laurylsulphonate salts and the like.For a description of possible salts, see, e.g., Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.

As used herein, “therapeutically effective amount” means an amountsufficient to treat a subject afflicted with a disease (e.g. aneurodegenerative disease) or to alleviate a symptom or a complicationassociated with the disease.

As used herein, a “neurodegenerative disease” refers to a disease inwhich degeneration occurs of either gray or white matter, or both, ofthe nervous system. Thus, such a disease can be diabetic neuropathy,senile dementias, Alzheimer's disease, Mild Cognitive Impairment (MCI),dementia, Lewy Body Dementia, Frontal Temporal Lobe dementia,Parkinson's Disease, facial nerve (Bell's) palsy, glaucoma, Huntington'schorea, amyotrophic lateral sclerosis (ALS), status epilepticus,non-arteritic optic neuropathy, intervertebral disc herniation, vitamindeficiency, prion diseases such as Creutzfeldt-Jakob disease, carpaltunnel syndrome, peripheral neuropathies associated with variousdiseases, including but not limited to, uremia, porphyria, hypoglycemia,Sjorgren Larsson syndrome, acute sensory neuropathy, chronic ataxicneuropathy, biliary cirrhosis, primary amyloidosis, obstructive lungdiseases, acromegaly, malabsorption syndromes, polycythemia vera, IgAand IgG gammapathies, complications of various drugs (e.g.,metronidazole) and toxins (e.g., alcohol or organophosphates),Charcot-Marie-Tooth disease, ataxia telangectasia, Friedreich's ataxia,amyloid polyneuropathies, adrenomyeloneuropathy, Giant axonalneuropathy, Refsum's disease, Fabry's disease and lipoproteinemia.

As used herein, “tauopathies” refers to a class of neurodegenerativediseases which result from aggregation of tau protein in neurofibrillarytangles. Examples of tauopathies include, but are not limited to,Alzheimer's disease, Frontotemproal dementia (Pick's disease),Progressive Supranuclear Palsy, and Corticobasal degeneration.

As used herein, “treating” means slowing, stopping or reversing theprogression of a disease, particularly a neurodegenerative disease.

As used herein, “zwitterion” means a compound that is electricallyneutral but carries formal positive and negative charges on differentatoms. Zwitterions are polar, have high solubility in water have poorsolubility in most organic solvents.

The compounds disclosed herein may also form zwitterions. For example, acompound having the structure

may also for the following zwitterionic structure

where X is as defined throughout the disclosures herein.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. Thus, C₁-C_(n) as in “C₁-C_(n) alkyl”is defined to include groups having 1, 2, . . . , n−1 or n carbons in alinear or branched arrangement, and specifically includes methyl, ethyl,propyl, butyl, pentyl, hexyl, and so on. An embodiment can be C₁-C₁₂alkyl. “Alkoxy” represents an alkyl group as described above attachedthrough an oxygen bridge.

The term “alkenyl” refers to a non-aromatic hydrocarbon radical,straight or branched, containing at least 1 carbon to carbon doublebond, and up to the maximum possible number of non-aromaticcarbon-carbon double bonds may be present. Thus, C₂-C_(n) alkenyl isdefined to include groups having 1, 2, . . . , n−1 or n carbons. Forexample, “C₂-C₆ alkenyl”, means an alkenyl radical having 2, 3, 4, 5, or6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, forexample, 3 carbon-carbon double bonds in the case of a C₆ alkenyl,respectively. Alkenyl groups include ethenyl, propenyl, butenyl andcyclohexenyl. As described above with respect to alkyl, the straight,branched or cyclic portion of the alkenyl group may contain double bondsand may be substituted if a substituted alkenyl group is indicated. Anembodiment can be C₂-C₁₂ alkenyl.

The term “alkynyl”, refers to a hydrocarbon radical straight orbranched, containing at least 1 carbon to carbon triple bond, and up tothe maximum possible number of non-aromatic carbon-carbon triple bondsmay be present. Thus, C₂-C_(n) alkynyl is defined to include groupshaving 1, 2, . . . , n−1 or n carbons. For example, “C₂-C₆ alkynyl”means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbontriple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbontriple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triplebonds. Alkynyl groups include ethynyl, propynyl and butynyl. Asdescribed above with respect to alkyl, the straight or branched portionof the alkynyl group may contain triple bonds and may be substituted ifa substituted alkynyl group is indicated. An embodiment can be aC₂-C_(n) alkynyl.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 10 atoms in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthrylor acenaphthyl. In cases where the aryl substituent is bicyclic and onering is non-aromatic, it is understood that attachment is via thearomatic ring. The substituted aryls included in this invention includesubstitution at any suitable position with amines, substituted amines,alkylamines, hydroxys and alkylhydroxys, wherein the “alkyl” portion ofthe alkylamines and alkylhydroxys is a C₂-C_(n) alkyl as definedhereinabove. The substituted amines may be substituted with alkyl,alkenyl, alkynl, or aryl groups as hereinabove defined.

The alkyl, alkenyl, alkynyl, and aryl substituents may be unsubstitutedor unsubstituted, unless specifically defined otherwise. For example, a(C₁-C₆) alkyl may be substituted with one or more substituents selectedfrom OH, oxo, halogen, alkoxy, dialkylamino, or heterocyclyl, such asmorpholinyl, piperidinyl, and so on.

In the compounds of the present invention, alkyl, alkenyl, and alkynylgroups can be further substituted by replacing one or more hydrogenatoms by non-hydrogen groups described herein to the extent possible.These include, but are not limited to, halo, hydroxy, mercapto, amino,carboxy, cyano and carbamoyl. The term “substituted” as used hereinmeans that a given structure has a substituent which can be an alkyl,alkenyl, or aryl group as defined above. The term shall be deemed toinclude multiple degrees of substitution by a named substitutent. Wheremultiple substituent moieties are disclosed or claimed, the substitutedcompound can be independently substituted by one or more of thedisclosed or claimed substituent moieties, singly or plurally. Byindependently substituted, it is meant that the (two or more)substituents can be the same or different.

As used herein, “administering” an agent may be performed using any ofthe various methods or delivery systems well known to those skilled inthe art. The administering can be performed, for example, orally,parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery, subcutaneously, intraadiposally, intraarticularly,intrathecally, into a cerebral ventricle, intraventicularly,intratumorally, into cerebral parenchyma or intraparenchchymally.

The following delivery systems, which employ a number of routinely usedpharmaceutical carriers, may be used but are only representative of themany possible systems envisioned for administering compositions inaccordance with the invention.

Injectable drug delivery systems include solutions, suspensions, gels,microspheres and polymeric injectables, and can comprise excipients suchas solubility-altering agents (e.g., ethanol, propylene glycol andsucrose) and polymers (e.g., polycaprylactones and PLGA's).

Implantable systems include rods and discs, and can contain excipientssuch as PLGA and polycaprylactone.

Oral delivery systems include tablets and capsules. These can containexcipients such as binders (e.g., hydroxypropylmethylcellulose,polyvinyl pyrilodone, other cellulosic materials and starch), diluents(e.g., lactose and other sugars, starch, dicalcium phosphate andcellulosic materials), disintegrating agents (e.g., starch polymers andcellulosic materials) and lubricating agents (e.g., stearates and talc).

Transmucosal delivery systems include patches, tablets, suppositories,pessaries, gels and creams, and can contain excipients such assolubilizers and enhancers (e.g., propylene glycol, bile salts and aminoacids), and other vehicles (e.g., polyethylene glycol, fatty acid estersand derivatives, and hydrophilic polymers such ashydroxypropylmethylcellulose and hyaluronic acid).

Dermal delivery systems include, for example, aqueous and nonaqueousgels, creams, multiple emulsions, microemulsions, liposomes, ointments,aqueous and nonaqueous solutions, lotions, aerosols, hydrocarbon basesand powders, and can contain excipients such as solubilizers, permeationenhancers (e.g., fatty acids, fatty acid esters, fatty alcohols andamino acids), and hydrophilic polymers (e.g., polycarbophil andpolyvinylpyrolidone). In one embodiment, the pharmaceutically acceptablecarrier is a liposome or a transdermal enhancer.

Solutions, suspensions and powders for reconstitutable delivery systemsinclude vehicles such as suspending agents (e.g., gums, zanthans,cellulosics and sugars), humectants (e.g., sorbitol), solubilizers(e.g., ethanol, water, PEG and propylene glycol), surfactants (e.g.,sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine), preservativesand antioxidants (e.g., parabens, vitamins E and C, and ascorbic acid),anti-caking agents, coating agents, and chelating agents (e.g., EDTA).

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art fromreadily available starting materials. If a substituent is itselfsubstituted with more than one group, it is understood that thesemultiple groups may be on the same carbon or on different carbons, solong as a stable structure results.

The compounds disclosed herein (Compounds 100-108, Compounds 100E to108E, Compound 201, Compounds 203-214 and Compound 207(a)) were obtainedfrom Lixte Biotechnology Holdings, Inc., 248 Route 25A, No. 2, EastSetauket, N.Y.

Discussion

The compounds described herein are useful for the prevention and/ortreatment of neurodegenerative conditions including Alzheimer's disease,Parkinson's disease, motor neuron diseases such as amyotrophic lateralsclerosis, and other neurodegenerative diseases collectively known astauopathies.

Several of the compounds inhibit protein phosphatase 2A. These includeCompounds 100, 102, 103, 104, 105, 106, 107, 108, 111, the structures ofwhich are shown in Table 1. These compounds differ in substituents onportions of the core molecule Compound 100. These compounds show dosedependent inhibition of a broad spectrum of human cancer cell lines invitro including SH-SY5Y, a dopaminergic neuronal line, frequently usedas a model for assessing pharmacologic interventions relevant to humanneuronal cells. Given intraperitoneally, these compounds enter the brainof the normal mouse as demonstrated by increased acetylation of histone3 and 8.

The compounds increase the phosphorylation of several regulatoryproteins including Akt. At low doses that are non-toxic to mice, thesecompounds slightly stimulate cell proliferation and increasesphosphorylation of Akt in human cancer cell lines tested includingSH-SY5Y. When given intraperitoneally to normal mice, Compound 100 andCompound 102 also increased Akt phosphorylation in the cell linestested, growing as xenografts in SCID mice, as set forth in the examplesherein.

Because the Compound-100 series of drugs increase cellularphosphorylated Akt at low non-toxic doses and also increase acetylationof histones in neurons of the intact animal, these compounds are usefulfor the treatment of neurodegenerative diseases, particularlyAlzheimer's disease and all other tauopathies. While each of thecompounds tested increase Akt phosphorylation of multiple tumor celllines, they also increase Akt phosphorylation of the neuroblastoma cellline SH-SY5Y, a model of dopamine neurons.

The results with Compound 100 and Compound 102 show that each of thesehas properties that enhance their entry into the brain. Thus, thesedrugs are neuroprotective and useful for the prevention and/or treatmentof neurodegereratve disease. The mechanism by which the Compound 100series of compounds exert their neuroprotective effect may be byincreasing the intra-neuronal cell activity of Akt-1 and enhancing thephosphorylation of GSK-3B. Each of these compounds when given byintraperitoneal injection, increase Akt phosphorylation in mouseneurons. This increase in Akt phosphorylation is associated with anincrease in the phosphorylation of GSK-3β. Increased phosphorylation ofGSK-3β is known to decrease its activity. Therefore, chronic suppressionof GSK-3β activity by compound 100 homologs may reduce tauphosphorylation. Reduction in tau phosphorylation reduces the formationof paired helical filaments, an intervention that should lessen theprogression of tauopathies including Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, and other rarerneurodegenerative diseases characterized by abnormal depositions of taumolecules. The compound 200 series, which include compounds 201, 207(a)and 203-214, the structures of which are shown in Table 2, are HDACinhibitors.

TABLE 1 Compouns 100-108 and 111 Compound 100

Compound 100E

Compound 101

Compound 101E

Compound 102

Compound 102E

Compound 103

Compound 103E

Compound 104

Compound 104E

Compound 105

Compound 105E

Compound 106

Compound 106E

Compound 107

Compound 107E

Compound 108

Compound 108E

Compound 111

TABLE 2 Compound Structure 201

203

204

205

206

207

207a

208

209

210

211

212

213

214

Experimental Details

First Series of Experiments

In Vivo Experiments

Human medulloblastoma DAOY cells were implanted subcutaneously in SCIDmice. Mice were then treated with 0.03 mg/20 gram mouse with Compound100 or vehicle alone. After 4 hours and 24 hours, western blots weremade for phosphorylated Akt (p-Akt), total Akt, and beta actin. Controlcells at both time points had only trace amount of p-Akt and substantialamounts of total Akt and beta actin. Exposure to compound 100 revealedinduction of p-Akt and an increase in total Akt relative to beta actin,as shown in FIG. 3.

Human glioblastoma U87 cells were implanted subcutaneously in SCID mice.Mice were then treated with 0.03 mg/20 gram mouse with Compound 100 orvehicle alone. After 4 hours, western blots were made for p-Akt, totalAkt, and beta actin. Control cells showed only trace amounts of p-Aktand substantial amounts of total Akt and beta actin. Exposure toCompound 100 revealed induction of p-Akt and an increast in total Aktrelative to beta actin, as shown in in FIG. 5.

Normal mice were treated with Compound 100 or Compound 102 at a dose of0.03 mg/20 gram mouse, or with vehicle. After 4 hours of exposure,treated and control animals were sacrificed and western blots foracetylated histone 3 and histone 4 were made. As showin in FIG. 6, bothdruges increased acetylation of the histones compared to control tissue.

In Vitro Experiments:

Medulloblastoma cells, DAOY, were grown in culture and exposed toCompound 100, Compound X or vehicle alone. After 4 hours western blotswere made for p-Akt, total Akt and beta actin. Control cells showed onlytrace amounts of p-Akt and substantial amounts of total Akt and betaactin. Exposure to the control agent Compound 205, an investigationalhistone deacetylase inhibitor, had little effect. Exposure to Compound100 revealed induction of p-Akt and an increase in total Akt relative tobeta actin.

Human glioblastoma cells, U87, were grown in culture and exposed toCompound 100 or vehicle alone. After 4 hours, western blots were madefor p-Akt, total Akt, and beta actin. Control cells showed only traceamounts of p-Akt and substantial amounts of total Akt and beta actin.Exposure to Compound 100 revealed induction of p-Akt and an increase intotal akt relative to beta actin, as shown in FIG. 4.

Neuroprotective and neurotrophic effects of a novel HDAC inhibitor,compound 201, and a novel protein phosphatase 2A inhibitor, compound102, on primary rat cortical neurons.

The effects of two novel compounds, compound 201, a class I and II HDACinhibitor (HDACi), and compound 102, a protein phosphatase 2A inihibitor(PP2Ai), on neuronal cell characteristics including physiologicalresponses to signalling agents, differentiation and maturation inculture, and survival following environmental stress were investigated.Neurite extension was evaluated after Calcein staining usingcommercially available software. Exposure to either compound 201 orcompound 102 at 250 and 500 nM resulted in increased total neuriteoutgrowth and increased process length and then was evaluated for theirability to sustain neuron integrity over time after exposure to stress.

Neurons were chronically or acutely treated with each compound andexposed to environmental stress (replacement of the culture medium witha saline PBS based solution for one hour followed by removal of the PBSmedium and restoration of standard neuronal culture medium) and thenobserved for survival (FIG. 6). Compound 201 displayed markedneurotrophic effects as evidenced by maintenance for up to 21 daysneuronal cell numbers. In contrast, cells exposed to either DMSO (thevehicle used for the compounds) or just saline showed a 3.5 foldreduction in cell numbers (FIG. 7). Compound 102 had little effect oncell number. To assess the effects of compound 102 and compound 201,independently, on neuronal function, the ability of the neurons in aculture dish to respond to exposure to glutamate was studied. In vitro,neurons respond to glutamate with the activation of several receptorsassociated with different transducing mechanisms. The assortment ofglutamate sensitive receptors in a given neuronal population depends onmaturation and differentiation. After seven days in culture, there is anassortment of glutamate receptors, including the AMPA/Kainate and NMDAreceptors. AMPA/Kainate receptors are in general maximally expressed inthe first few days in vitro followed by a gradual decline, while NMDAreceptor expression increases over time, reaching a maximum after 7 daysin vitro. AMPA/Kainate responses to exposure to glutamate as measured bycalcium flux are characterized by fast desensitization (i.e. very littlemeasurable calcium increase), while NMDA responses are characterized byan elevation of calcium concentration that persists as long as glutamateis applied. In the absence of test drug, there was variability inglutamate responsiveness dependent on NMDA receptor expression. Atypical response of neurons in culture to glutamate characteristic ofthe NMDA receptors consists of a rapid increase and a high plateau phaseof calcium (FIGS. 8-10). Repeat experiments showed variability in theextent of this response indicating that the time-point in culture is amoment at which NMDA receptor expression is variable. Exposures to 500nM compound 201 (FIGS. 11-14) and, independently, to 500 nM compound 102(FIGS. 15-18) for 24 h prior exposure to glutamate, however, wereassociated with a statistically significant increase in the NMDA typeresponse to glutamate (p<=0.001), particularly in neurons showing thesmallest response to glutamate (FIGS. 11-14). This modulation iscompatible with a positive neurotrophic effect of compound 201. Asimilar smaller but statistically significant effect (p<=0.01) wasassociated with compound 102 (FIG. 19).

REFERENCES

-   1. Burke, R. E., Pharmacology and Therapeutics (2007) 114:262-277.-   2. Schapira, A. H. V. and Olanow, C. W., JAMA (2004) 291:358-364-   3. Ries, V. et al., PNAS (2006) 103:18757-18762-   4. Sontag, E et al., Neuron (1996) 17:1201-1207-   5. Tian, Q. and Wang, J., Neurosignals (2002) 11:262-269-   6. Gong et al 2005 J Neural Transm. (2005) 112(6):813-38-   7. Meske, V. et al., The Journal of Biological Chemistry, (2008)    283:100-109.-   8. Grimes and Jope, Progress In Neurobiology (2001) 65:391-426-   9. Liu, F. et al., Journal of Neurochemistry (2005) 95:1363-1372-   10. Kaytor, M. D. and Orr, H. T. Current Opinion in    Neurobiology (2002) 12:275-278-   11. Baki, L. et al, The Journal of Neuroscience (2008)-   12. Shen, J. et al., Cell (1997) 89:629-639-   13. Wong, P. C. et al., Adv. Exp. Med. Biol. (1998) 446:145-159-   14. Sherrington, R. et al., Nature (1995) 375:754-760-   15. Baki, L. et al., The EMBO Journal (2004) 23:2586-2596-   16. Kang, D. E. et al., The Journal of Biological Chemistry (2005)    280:31537-31547-   17. Uemura, K. et al., The Journal of Biological Chemistry (2007)    282:15823-18832-   18. Engel, T. et al., The Journal of Neurosciences (2006)    26:5083-5090-   19. Korzus, E. et al., Neuron (2004) 42:961-972-   20. Levenson, J. M. et al., The Journal of Biological    Chemistry (2004) 279:40545-40559-   21. Beglopoulos, V. and Shen, J., TRENDS in Pharmacological    Sciences (2006) 27:33-40-   22. Fischer, A. et al., Nature (2007) 447:178-182;    doi:1038/nature05772-   23. Sweat, J. D. et al., Nature (2007) 447:151-152-   24. Mangan, K. P. and Levenson, J. M., Cell (2007) 129:851-853-   25. Albert, M. S., New Engl. J. Med. (2007) 357(5):502-503-   26. Abel, T and Zukin, R. S., Current Opinion in Pharmacology (2008)    8:57-64

1. A method of treating a subject with a neurodegenerative disease comprising administering to the subject a compound having the structure

wherein bond α is present or absent; R₁ and R₂ is each independently H, O⁻ or OR₉, where R₉ is H, alkyl, alkenyl, alkynyl or aryl, or R₁ and R₂ together are ═O; R₃ and R₄ are each different, and each is OH, O⁻, OR₉, SH, S⁻, SR₉,

where X is O, S, NR₁₀, or N⁺R₁₀R₁₀, where each Rlo is independently H, alkyl, substituted C₂-C₁₂ alkyl, alkenyl, substituted C₄-C₁₂ alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl where the substituent is other than chloro when R₁ and R₂ are ═O,

—CH₂CN, —CH₂CO₂R₁₁, —CH₂COR₁₁, —NHR₁₁ or —NH⁺(R₁₁)₂, where each R₁₁ is independently alkyl, alkenyl or alkynyl, each of which is substituted or unsubstituted, or H; R₅ and R₆ is each independently H, OH, or R₅ and R₆ taken together are ═O; and R₇ and R₈ is each independently H, F, Cl, Br, SO₂Ph, CO₂CH₃, or SR₁₂, where R₁₂ is H, aryl or a substituted or unsubstituted alkyl, alkenyl or alkynyl, or a salt, enantiomer or zwitterion of the compound or a compound having the structure

wherein n is 1-10; Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂, trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl; z is

R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl; R₂₄ is OH or SH; and R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl, SO₂R₃₄, NO₂, trifluoromethyl, methoxy, or CO—R₃₄, wherein R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl, or a salt of the compound, in an amount effective to treat the subject.
 2. The method of claim 1, wherein the subject is a human.
 3. The method of claim 1, wherein the neurodegenerative disease is Alzheimer's disease, Mild Cognitive Impairment, Parkinsons Disease, Frontotemporal Dementia, Dementia, or Lewy Body Dementia.
 4. The method of claim 3, wherein the neurodegenerative disease is Alzheimer's disease.
 5. The method of claim 4, comprising further administering to the subject an NMDA receptor antagonist, an acetylcholinesterase inhibitor, an anti-amyloid antibody, a 5-HT6 antagonist, a gamma secretase inhibitor, a beta secretase inhibitor, or an inhibitor of aggregation of amyloid-β peptide.
 6. The method of claim 5, comprising further administering to the subject a tau aggregation inhibitor.
 7. The method of claim 3, wherein the neurodegenerative disease is Parkinson's disease.
 8. The method of claim 7, comprising further administering to the subject a dopamine receptor agonist.
 9. A method for reducing the amount of active GSK-3B or increasing the amount of phosphorylated Akt in a neural cell comprising contacting the cell with an effective amount of a compound having the structure

wherein bond α is present or absent; R₁ and R₂ is each independently H, O⁻ or OR₉, where R₉ is H, alkyl, alkenyl, alkynyl or aryl, or R₁ and R₂ together are ═O; R₃ and R₄ are each different, and each is OH, O⁻, OR₉, SH, S⁻, SR₉,

where X is O, S, NR₁₀, or NR₁₀R₁₀, where each R₁₀ is independently H, alkyl, substituted C₂-C₁₂ alkyl, alkenyl, substituted C₄-C₁₂ alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl where the substituent is other than chloro when R₁ and R₂ are ═O,

—CH₂CN, —CH₂CO₂R₁₁, —CH₂COR₁₁, —NHR₁₁ or —NH⁺(R₁₁)₂, where each R₁₁ is independently alkyl, alkenyl or alkynyl, each of which is substituted or unsubstituted, or H; R₅ and R₆ is each independently H, OH, or R₅ and R₆ taken together are ═O; and R₇ and R₈ is each independently H, F, Cl, Br, SO₂Ph, CO₂CH₃, or SR₁₂, where R₁₂ is H, aryl or a substituted or unsubstituted alkyl, alkenyl or alkynyl, or a salt, enantiomer or zwitterion of the compound or a compound having the structure

wherein n is 1-10; Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂, trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl; z is

R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl; R₂₄ is OH or SH; and R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl, SO₂R₃₄, NO₂ trifluoromethyl, methoxy, or CO—R₃₄, wherein R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl, or a salt of the compound, so as to thereby reduce the amount of GSK-3B or increase the amount of phosphorylated Akt in the neural cell.
 10. (canceled)
 11. A method for reducing the phosphorylation or aggregation of Tau protein in a cell, comprising contacting the cell with an effective amount of a compound having the structure

wherein bond α is present or absent; R₁ and R₂ is each independently H, O⁻¹ or OR₉, where R₉ is H, alkyl, alkenyl, alkynyl or aryl, or R₁ and R₂ together are ═O; R₃ and R₄ are each different, and each is OH, O⁻, OR₉, SH, S⁻, SR₉,

where X is O, S, NR₁₀, or N⁺R₁₀R₁₀, where each R₁₀ is independently H, alkyl, substituted C₂-C₁₂ alkyl, alkenyl, substituted C₄-C₁₂ alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl where the substituent is other than chloro when R₁ nd R₂ are ═O,

—CH₂CN, —CH₂CO₂R₁₁, —CH₂COR₁₁, —NHR₁₁ or —NH⁺(R₁₁)₂, where each R₁₁ is independently alkyl, alkenyl or alkynyl, each of which is substituted or unsubstituted, or H; R₅ and R₆ is each independently H, OH, or R₅ and R₆ taken together are ═O; and R₇ and R₈ is each independently H, F, Cl, Br, SO₂Ph, CO₂CH₃, or SR₁₂, where R₁₂ is H, aryl or a substituted or unsubstituted alkyl, alkenyl or alkynyl, or a salt, enantiomer or zwitterion of the compound, or a compound having the structure

wherein n is 1-10; Y is C—R₃₀ or N, wherein R₃₀ is H, OH, SH, F, Cl, SO₂R₂₆, NO₂, trifluoromethyl, methoxy, or CO—R₂₆, wherein R₂₆ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl; z is

R₂₁ is H or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are each independently H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl; R₂₄ is OH or SH; and R₂₅, R₃₁, R₃₂, and R₃₃ are each independently H, OH, SH, F, Cl, SO₂R₃₄, NO₂, trifluoromethyl, methoxy, or CO—R₃₄, wherein R₃₄ is alkyl, alkenyl, alkynyl, C₃-C₈ cycloalkyl, or aryl, or a salt of the compound, so as to thereby reduce the phosphorylation or aggregation of tau in the cell.
 12. (canceled)
 13. The method of claim 11, wherein the cell is a neural cell.
 14. The method of claim 11, wherein the cell is in a subject.
 15. The method of claim 1, wherein the compound has the structure 